Cancer is one of the most widespread diseases affecting mankind, and a leading cause of death worldwide. In the United States alone, cancer is the second leading cause of death, surpassed only by heart disease. Cancer is often characterized by deregulation of normal cellular processes or unregulated cell proliferation. Cells that have been transformed to cancerous cells tend to proliferate in an uncontrolled and unregulated manner leading to, in some cases, metastisis or the spread of the cancer. Deregulation of the cell proliferation could result from the modification to one or more genes, responsible for the cellular pathways that control cell-cycle progression. Or it could result from DNA modifications (including but not limited to mutations, amplifications, rearrangements, deletions, and epigenetic gene silencing) in one or more cell-cycle checkpoint regulators which allow the cell to move from one phase of the cell cycle to another unchecked.
Somatic cell division is a complex and highly coordinated process that ensures faithful segregation of duplicated chromosomes into two daughter cells. Deregulation of the cell cycle is a hallmark of cancer, characterized by uncontrolled proliferation and defects in chromosome segregation. Mitosis is the process by which a eukaryotic cell segregates its duplicated chromosomes into two identical daughter nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membranes into two daughter cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define the mitotic (M) phase of the cell cycle—the division of the mother cell into two daughter cells, genetically identical to each other and to their parent cell.
The process of mitosis is complex and highly regulated. The sequence of events is divided into distinct phases, corresponding to the completion of one set of activities and the start of the next. These stages are prophase, prometaphase, metaphase, anaphase and telophase. During the process of mitosis duplicated chromosomes condense and attach to fibers that pull the sister chromatids to opposite sides of the cell. The cell then divides in cytokinesis, to produce two identical daughter cells. Errors in mitosis can either kill a cell through apoptosis or cause mis-segratation of chromosomes that may lead to cancer.
Normally, cell-cycle checkpoints are activated if DNA errors are detected (e.g. DNA damage). If these errors to the genome cannot be fixed, the cell normally undergoes apoptosis. However, if the cell is allowed to move through its cell-cycle and progress unchecked, then more mutations can accumulate over time. These gene modifications can accrue and eventually leading cell progeny with pre-malignant or malignant neoplastic characteristics (e.g. uncontrolled proliferation) through adaptation.
Antimitotic drugs that block tumor cell division are a proven intervention strategy in the treatment of cancer. However, the clinical benefits of classical antimitotic drugs may be hampered by development of multidrug resistance (MDR) and collateral damage to non-dividing cells including for example, peripheral neuropathy (Quasthoff S. et al, Chemotherapy-Induced Peripheral Neuropathy, J. Neurol. 249: 9-17, 2002).
Aurora kinases are essential mitotic regulators and their potential role in tumorigenesis makes them attractive targets for anticancer therapy (Keen N. et al, Aurora-kinase Inhibitors as Anti-cancer Agents, Nat. Rev. Cancer, 4:927-936, 2004; Keen N. et al, Mitotic Drivers—Inhibitors of the Aurora B Kinase, Cancer Met. Rev., 28:185-195, 2009; and Carvahjal R D. et al, Aurora-Kinases: New Targets for Cancer Therapy, Clin. Cancer Res. 12:6869-6875, 2006). In mammalian cells, the aurora family of serine/threonine protein kinases is comprised of three paralogous genes (aurora-A, -B, and -C). Aurora-A and -B are essential regulators of mitotic entry and progression, whereas aurora-C function is primarily restricted to male meiosis during spermatogenesis. Aurora-A can function as an oncogene and is amplified in a subset of human tumors. Aurora-A and -B expression is frequently elevated in human cancers and is associated with advanced clinical staging (Gautschi et al, Clin. Cancer Res., 14:1639-1648, 2008). The mitotic checkpoint, also referred to as the spindle assembly checkpoint (SAC), is a surveillance mechanism responsible for controlling proper alignment, microtubule-kinetochore attachments, and segregation of duplicated chromosomes. In tumor cells, genetic depletion or pharmacological inhibition of aurora-A results in abnormal spindle formation and SAC activation. In constrast, depletion or inhibition of aurora-B inactivates the SAC, resulting in aborted cell division without a mitotic arrest. Importantly, dual suppression of aurora-A and -B appears to phenocopy the effects of inhibiting aurora-B alone (Hauf S. et al., J. Cell Biol. 161:281-194, 2003; and Yang H. et al, FEBS Letters, 579:3385-3391, 2005). The silencing of the SAC leads to an accumulation of tumor cells that contain 4N DNA content in the G1-phase of the cell cycle. Continued suppression of aurora-B activity leads to further rounds of genome replication without division, a process referred to as endoreduplication, which ultimately results in tumor cell death (Girdler F. et al, J. Cell Sci., 119:3664-3675, 2006).
The therapeutic window is very important for the success of a drug in treating a patient. Generally, the pharmacokinetic (PK) and pharmacodynamic (PD) factors of a given drug will help determine what the therapeutic window for that drug may be, in a subject or in an animal or human. Pharmacokinetic factors include, for example, plasma (blood) drug concentration per unit time; tissue drug concentration (per unit time); drug metabolism including, without limitation, the absorption, distribution (in both tissues and serum); protein binding, clearance, elimination, drug interactions and the like, of the drug; route of clearance; and drug half life, to name a few. Pharmacodynamic factors involve factors relating to the desired therapeutic effect of the drug and/or the duration of action of the drug on the target. For instance, some pharmacodynamic factors include, without limitation, binding affinity or potency of the drug for the receptor(s) or target(s); reaction dynamics between the drug and the biological target; mode of action of the drug on the target.
Other factors influencing the therapeutic window of a drug include and, therefore the successful treatment of the patient with the drug, for instance, body size, age, gender, route of administration, time of administration, tolerance, barometric pressure, gastrointestinal function, fever, liver function, diet; stress, breastfeeding, other drugs, disease, cardiovascular function, starvation, exercise, age, sunlight, pregnancy, immunologic function, kidney function, genetic make-up, immunization, alcohol intake, albumin level in the blood, smoking, and weight. These are but a few considerations that doctors must consider when prescribing a drug with the objective of providing the maximum benefit to the patient.
Each of these factors play a role, complexly interwoven, in attempting to determine whether or not a drug has a therapeutic window in subjects, such as in humans, and if one does exists, how wide or how large that therapeutic dosage range or window of therapeutic beneficial effect it may be. It is known that generally in order for a drug to possess a sufficient therapeutic margin, it must have sufficient target coverage. That is, it must be acting on the biological target at a sufficient concentration and over a sufficient time period, per day, to drive the beneficial/therapeutic effect on the disease or condition, while not inducing or causing an unacceptable level of undesired and/or untreatable side effects. Despite some understanding in general of how many of these factors influence one another in-vivo, every drug, i.e., every molecule per se is a different structure and has its own distinct pK and PD profiles and, to this end, will have a unique and unpredictable in-vivo safety and efficacy profile.
Historically, the task of finding a suitable therapeutic window for a specific molecule, and one that provides sufficient confidence in success to justify the investment and time, has been difficult and very unpredictable in nature. First, therapeutic windows in which to administer a drug is unique to that particular molecule. Second, this window must be shown to be statistically significant and meaningful in human clinical trials, which take years to enroll and complete and required a great amount of time, resources and investment without any certainty of success.
There have been a few aurora kinase targeted therapeutics clinically tested. Each was found to possess a different potential therapeutic window, if one was identified at all. For instance, Danusertib (PHA-739358), a pan-aurora kinase inhibitor, was dosed in a Ph I trial to assess its safety, tolerability, pharamcokinetics and pharmacodynamic profile. Dosing schedule began with a 24 hour infusion every 14 days. It was concluded from the trial that danusertib can be safely administered to patients with advanced refractory solid tumors upto an amount of 500 mg/m2 over 24 hours in a 14 day cycles without GCSF. Within this dose, danusertib was found to provide “prolonged objective response in small cell lung carcinoma and multiple instance of prolonged disease stabilization in other solid tumors (Cohen et al, Clinical Cancer Res., 15(21), 2009). Thus, a therapeutic window was identified for this potential drug.
Another example is the study of PF-03814735, an oral auaroa kinse inhibitor in a Ph I study for pK and PD in patients with advanced solid tumor. In that trial PF-03814735 was administered in a daily dosing schedule of 5 or 10 consecutive days in 3-week cycles. This means that the inhibitor was dosed for either 5 consecutive days followed by 16 days without any dosing, or for 10 consecutive days followed by 11 days without any drug. Patients had various solid tumors, including colorectal, breast, non-small cell lung cancer, small cell lung cancer, bladder, melanoma, ovarian, renal, and head and neck tumors. A safety margin for PF-03814735 was identified, as adverse events began to be observed during the dose escalation phase. However, the dosing schedule tested provided NO objective response on the tumors. Thus, no therapeutic window for that particular dosing schedule was identified for this specific molecule (Jones et al., J. Clin. Onc. Vol. 26, 2008). The dosages administered were raised in certain circumstances in a hope to identify a therapeutic window.
Yet another example of how unpredictable it is to identify a suitable therapeutic window for a given molecule is that of Renshaw and co-workers. Renshaw and colleagues disclosed some results from the Ph I trial of AS703569 (R763), an orally available aurora kinase inhibitor in subjects with solid tumors. The compounds was administered according to two dosing regimens over a 3-week or 12 day cycle: (1) dosing on days 1 and 8, i.e., dose for one day on day 1 followed by off for days 2-7, then dose again on day 8, followed by no dosing on days 9-21 to complete the cycle; and (2) consecutive dosing on days 1, 2 and 3, followed by no dosing on days 4-21 of the 3-week cycle. Patient solid tumors included uterine/cervical cancer and 2 cases of breast cancer. The drug was found to be tolerable at various dosages in the regimen schedules tested (Renshaw et al., J. Clin. Onc., vol 25, No. 18S, 2007). However, no positive impact(s) on the patient's solid tumors were reported. Hence, it is reasonable to conclude that no therapeutic window was identified for this compound due to a lack of any sign of drug efficacy on patient tumors.
Another example of that of MK-5108. MK-5108 is an aurora kinase inhibitor, selective for aurora A kinase. It was clinically tested in humans in a Ph I trial wherein the dosing schedule was as follows: the drug was orally administered every 12 hrs during the first 1 days of each cycle, and the cycle length was 14-21 days. Hence, patients received drug every 12 hours for 2 consecutive days and did not receive drug for the remaining 12 (or 19) days in the cycle (US Clinicaltrials.gov). It was ultimately determined that the product was maximally beneficial if administered in combination with docetaxol (IV; Mol. Cancer. Ther., 1 (9), 157-166, 2010). Hence, as a potential first line, stand alone therapeutic, no suitable therapeutic window was reported, and it is believed that one was not identified, for this molecule.
Another example is AZD1152, a specific-aurora kinase inhibitor, selective for auroroa B, was dosed in a Ph I trial to assess its safety, tolerability, pharamcokinetics and pharmacodynamic profile. Dosing schedule began with a 2 hour IV infusion every 7 days (weekly). It was concluded from the trial that AZD 1152 was safely administered to patients with advanced solid malignancies upto a dosage amount of 450 mg. Within this dose, AZD1152 was observed to “significantly stabilize disease” in patients with rapidly progressive diseases (Schellens et al, J. Clinical One., 24(18S), 2006). Thus, it was concluded that there was sufficient information to continue to develop the molecule, in the hope that a suitable therapeutic window would be identified.
Patient compliance with taking a particular drug is an important factor in the successful treatment of that patient's medical condition, state and/or disease. It doesn't necessarily matter, generally, whether or not that treatment is merely prophylactic or whether that treatment is either acute or chronic. Patients tend to follow treatment schedules or treatment regimens that are convenient, easy to administer and/or easily remembered. For example, oral dosage forms intended to be administered or taken by the patient once a day, with or without a meal, is generally regarded as a convenient regimen with a high likelihood of patient compliance. However, such a once-a-day regiment may not be optimal dosing period to address the patients' conditions, symptoms and/or disease, such as cancer. Thus, there is a need to identify the optimal dosage amount of a drug to be administered in a convenient dosing schedule or regimen, to provide best patient compliance with treatment for cancer.
AMG 900 is an orally bioavailable, potent and selective pan-aurora kinase inhibitor which has anti-cancer properties in tumor cells. Particularly, AMG 900 has exhibited uniform potency across various tumor cell lines, including P-gp and BCRP expressing cell lines. In vivo, AMG 900 blocks the phosphorylation of histone H3, a proximal substrate of aurora-B (Crosio C. et al, Mol. Cell. Bio. 22:874-885, 2002) and inhibits the growth of multiple tumor xenografts, including three MDR xenograft models resistant to paclitaxel or docetaxel. AMG 900 is presently under clinical evaluation in adult patients with cancer, including advanced solid tumors, and in adult patients with myelogenous leukemias, both acute (AML) and chronic (CML).
It is unknown what any specific anti-cancer therapeutic agent may afford with respect to being able to treat, or even improve upon and/or provide superior treatments for, cancer over the standard of care cancer treatment at the time of filing this application. To this end, there is always a need to develop the best, most effective dosing regiment for a given drug, to most effectively treat cancer while minimizing undesired side effects and patient non-compliance with the medication. In addition, there is a need to improve upon the current available treatments or provide better, more efficiaous treatment schedules, and/or more convenient or easier to comply with treatment regimens, for cancer patients.